Serotonin (5-hydroxytryptamine, 5-HT) is a central nervous system neurotransmitter which exerts its many physiological functions by interaction with specific 5-HT receptors. These 5-HT receptors have been grouped into several main classes. Among these main classes, the 5-HT1 class comprises receptors characterized by high affinity for serotonin. The 5-HT, class is itself divided into a subclass of receptors whose pharmacological characteristics and regional distributions in the central nervous system are distinct.
Clinical studies on compounds with agonist activity for serotoninergic receptors of the 5-HT1A subtype have shown that 5-HT1A agonists are effective in treating anxiety (J. Clin. Psychiatry, 1987, 48, 3S) and depression (Int. J. Neuropsychopharmacology, 1998, 1, 18). Furthermore, studies in animals have shown that 5-HT1A agonists have analgesic properties (Behav. Brain Res., 1995, 73, 1/2, 69) and neuroprotective properties (Arch. Int. Pharmacodyn., 1995, 329, 347).
Given the broad therapeutic potential of compounds with agonist activity for serotoninergic receptors of the 5-HT1A subtype, the discovery of novel compounds with such activity is of great interest in human clinical therapy.
Buspirone, a 5-HT1A agonist used clinically, has comparable affinity for the serotoninergic receptors of the 5-HT1A subtype and for the dopaminergic receptors of the D2 subfamily. Since the dopaminergic receptors of the D2 subfamily are involved in motor control and cognitive and neuroendocrine functions (La Lettre du Pharmacologue, 1997, 11, 3), substances that are active on the dopaminergic receptors of the D2 subfamily, such as buspirone, are thus liable to give rise to neurological and/or motor and/or neuroendocrine disorders (CNS Drug, 1996, 5, 215). Dopaminergic or antidopaminergic activity combined with 5-HT1A agonist activity therefore does not constitute a combination of properties that is desirable for an agent intended for treating neurological disorders that are sensitive to serotoninergic activation mediated by 5-HT1A receptors.
Patent WO 98/22459-A1 discloses pyrid-2-ylmethylamine derivatives of the general formula 
in which:
A, U, V and W are, inter alia, a hydrogen atom,
X represents a hydrogen or fluorine atom,
Y is a chlorine atom or a methyl radical,
z is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl radical.
These compounds are claimed as 5-HT1A agonists that are useful in treating disorders that are sensitive to serotoninergic agonists of the 5-HT1A subtype.
The present application relates to novel compounds corresponding to the general formula (1) 
in which:
X is a hydrogen, fluorine or chlorine atom, and to the addition salts and the hydrates of the addition salts of the compounds of general formula (1) with pharmaceutically acceptable mineral acids or organic acids.
The compounds of formula (1) differ from those disclosed in patent WO 98/22459-A1 by the presence of an additional methylene group between the pyridine nucleus and the secondary amine function. The incorporation of the additional methylene group is reflected by a decrease in the dissociation constant of water (Ka) for the compounds of formula (1), by a factor of ten on average, compared with that of the compounds disclosed in patent WO 98/22459-A1. Such an increase in basicity greatly modifies the absorption and distribution parameters and also the modes of in vivo transformation of the compounds of the invention compared with those of the compounds claimed in patent WO 98/22459-A1.
The advantage of the compounds of the invention lies both in their selectivity and in their 5-HT1A agonist activity in vivo, which are much greater than those of buspirone. In this respect, the compounds of the invention, which combine therapeutic efficacy with a low propensity to display adverse side effects of D2 dopaminergic origin such as, for example, neurological and/or motor and/or endocrine disorders, are useful in treating a host of pathologies involving serotoninergic dysfunction, in particular anxiety, depression, neurodegeneration and the perception of pain.
The selectivity is defined in the present application as being the ratio of the affinity constants (Ki) D2/Ki (5-HT1A).
The central 5-HT1A agonist activity of the compounds of the invention and of buspirone was evaluated, after oral administration to rats, by their ability to induce retraction of the animals"" lower lip (LLR), which is a sensitive and specific marker of central 5-HT1A agonist activity (Pharmacol. Biochem. Behav., 1989, 33, 821).
A subject of the invention is also pharmaceutical compositions containing, as active principle, at least one derivative of general formula (1) or one of its salts or hydrates of its salts in combination with one or more pharmaceutically acceptable excipients, adjuvants or vehicles. By way of example, mention may be made of inclusion complexes, in particular the inclusion complexes formed by the compounds of the invention with xcex2-cyclodextrins.
The pharmaceutical compositions according to the invention are compositions which may be administered orally, nasally, sublingually, rectally or parenterally. It is generally advantageous to formulate such pharmaceutical compositions in unit dose form. In this case, each dose comprises a predetermined amount of the active principle, combined with the appropriate vehicle, excipients and/or adjuvants, calculated to obtain a given therapeutic effect. As examples of unit dose forms which may be administered orally, mention may be made of tablets, gel capsules, granules, powders and oral suspensions or solutions.
The formulations that are suitable for the chosen form of administration are known and described, for example, in Remington, The Science and Practice of Pharmacy, 19th edition, 1995, Mack Publishing Company, and may thus be readily prepared by a person skilled in the art.
It is known that the dosage varies from one individual to another, depending on the nature and severity of the affliction, the chosen route of administration and the weight, age and sex of the patient, and consequently the effective doses will have to be determined as a function of these parameters by the specialist in the field. As a guide, the effective doses may range between 0.001 mg/kg and 100 mg/kg/day.
The compounds of general formula (1) may exist in several tautomeric forms. Such tautomeric forms, although not explicitly reported in the present application to simplify the graphic representation of the formulae, are nevertheless included in the field of application of the invention.
Finally, the invention covers the process for preparing the derivatives of general formula (1).
The compounds of formula (1) were prepared according to the reaction sequence indicated in Scheme A. 
Scheme A
The compounds of formula (2) were prepared according to a method similar to that used for the synthesis of (4-fluoro-4-hydroxymethyl-1-piperidyl) (3-chloro-4-fluorophenyl)methanone and disclosed in patent WO 98/22459-A1. Oxidation of the compound of formula (2), using an activated dimethyl sulfoxide (DMSO) derivative such as, for example, DMSO activated with the sulfur trioxide-pyridine complex or activated with oxalyl chloride, gives the 1-(3-chloro-4-X-benzoyl)-4-20 fluoropiperidine-4-carbaldehyde of formula (3). A reductive amination reaction of the aldehyde of formula (3) using 2-(2-aminoethyl)pyridine, which is commercially available, then gives the compound of formula (1). In the reductive amination reaction under consideration, the aldehyde (3) and the 2-(2-aminoethyl)pyridine are reacted in the appropriate solvent and the mixture is then treated with the reducing agent. The reducing agent under consideration may be a simple or complex boron hydride such as, for example, sodium or potassium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.